Pharmaceutical formulations comprising a pyridylaminoacetic acid compound

ABSTRACT

Provided is a pharmaceutical preparation for treatment or prevention of glaucoma or ocular hypertension, comprising 0.0003 to 0.01% (w/v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, or a salt thereof.

RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.16/211,839, filed on Dec. 6, 2018, now U.S. Pat. No. 10,702,511, whichis a Continuation of U.S. application Ser. No. 15/895,100, filed on Feb.13, 2018, now U.S. Pat. No. 10,179,127, which is a Continuation of U.S.application Ser. No. 15/212,592, filed on Jul. 18, 2016, now U.S. Pat.No. 9,943,510, which is a Continuation of U.S. application Ser. No.14/592,167, filed on Jan. 8, 2015, now U.S. Pat. No. 9,415,038, whichclaims priority to U.S. Provisional Application No. 61/925,882, filed onJan. 10, 2014, the entire contents of all of which are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to a pharmaceutical preparation containingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.

BACKGROUND ART

Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis a compound represented by the following formula (1), and is describedas one of an enormous number of pyridylaminoacetic acid compounds inPatent Literature 1.

Also, such an enormous number of pyridylaminoacetic acid compounds havean EP2 agonistic activity (refer to Patent Literature 2) and are thusexpected to have an intraocular pressure lowering effect, and asuggestion has been made that the compounds may be used as therapeuticagents for glaucoma (refer to Patent Literature 1). Note that the entirecontents of Patent Literatures 1 and 2 are incorporated herein byreference.

However, there is no description about which of such an enormous numberof pyridylaminoacetic acid compounds has an especially excellentintraocular pressure lowering effect and may be used as a therapeutic orpreventive agent for glaucoma, and there is no description at all abouthow the intraocular pressure lowering effect is influenced by thecontent of the compounds.

CITATION LIST Patent Literature

-   [Patent Literature 1] US Patent Application Publication No.    2012/0190852-   [Patent Literature 2] US Patent Application Publication No.    2011/0054172

SUMMARY OF INVENTION

An object of the present invention is to find which of an enormousnumber of pyridylaminoacetic acid compounds has an especially excellentintraocular pressure lowering effect and may be used as a therapeutic orpreventive agent for glaucoma or ocular hypertension or an intraocularpressure lowering agent, and to find how the found compound is usedand/or what dose of the compound is administrated to a patient (mainly,a human) in order to obtain an effective therapeutic or preventiveeffect.

To achieve the above-described objects, the present inventors haveconducted earnest studies. As a result, the inventors have found outthat isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof (hereinafter also referred to as “present compound”)has a particularly excellent intraocular pressure lowering effect andmay be used as a therapeutic or preventive agent for glaucoma or ocularhypertension or an intraocular pressure lowering agent. Further, theinventors have found out that a somewhat low content of the presentcompound exhibits a more excellent intraocular pressure lowering effectthan a high content of the present compound, and surprisingly, anespecially excellent intraocular pressure lowering effect is exhibitedwhen one or two drops of an eye drop containing the present compound ata concentration of from 0.001 to 0.01% (w/v), preferably from 0.001 to0.003% (w/v) are instilled to a human once or twice a day, and such ausage and/or dose achieves an effective therapeutic or preventiveeffect, and the inventors have brought the present invention intocompletion. As employed herein, the term “% (w/v)” refers to the mass(g) of an effective ingredient (here, the present compound) or anadditive (e.g. a surfactant, etc.) contained in 100 mL of an ophthalmicsolution. For example, 0.01% (w/v) of the present compound means thatthe content of the present compound in 100 mL of the ophthalmic solutionis 0.01 g.

Specifically, the present invention can relate to the followings.

(1) A pharmaceutical preparation for treatment or prevention of glaucomaor ocular hypertension, comprising 0.001 to 0.01% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(2) The pharmaceutical preparation described in (1), comprising 0.001 to0.003% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(3) The pharmaceutical preparation described in (1), comprising 0.0011to 0.0030% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(4) The pharmaceutical preparation described in (1), comprising 0.0011to 0.0029% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(5) The pharmaceutical preparation described in (1), comprising 0.0013to 0.0027% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(6) The pharmaceutical preparation described in (1), comprising 0.0015to 0.0025% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(7) The pharmaceutical preparation described in (1), comprising 0.0010%(w/v), 0.0011% (w/v), 0.0012% (w/v), 0.0013% (w/v), 0.0014% (w/v),0.0015% (w/v), 0.0016% (w/v), 0.0017% (w/v), 0.0018% (w/v), 0.0019%(w/v), 0.0020% (w/v), 0.0021% (w/v), 0.0022% (w/v), 0.0023% (w/v),0.0024% (w/v), 0.0025% (w/v), 0.0026% (w/v), 0.0027% (w/v), 0.0028%(w/v), 0.0029% (w/v) or 0.0030% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(8) The pharmaceutical preparation described in (1), comprising 0.0011%(w/v), 0.0012% (w/v), 0.0013% (w/v), 0.0014% (w/v), 0.0015% (w/v),0.0016% (w/v), 0.0017% (w/v), 0.0018% (w/v), 0.0019% (w/v), 0.0020%(w/v), 0.0021% (w/v), 0.0022% (w/v), 0.0023% (w/v), 0.0024% (w/v),0.0025% (w/v), 0.0026% (w/v), 0.0027% (w/v), 0.0028% (w/v), 0.0029%(w/v) or 0.0030% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(9) The pharmaceutical preparation described in (1), comprising 0.0011%(w/v), 0.0012% (w/v), 0.0013% (w/v), 0.0014% (w/v), 0.0015% (w/v),0.0016% (w/v), 0.0017% (w/v), 0.0018% (w/v), 0.0019% (w/v), 0.0020%(w/v), 0.0021% (w/v), 0.0022% (w/v), 0.0023% (w/v), 0.0024% (w/v),0.0025% (w/v), 0.0026% (w/v), 0.0027% (w/v), 0.0028% (w/v) or 0.0029%(w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,or a salt thereof.

(10) The pharmaceutical preparation described in any of (1) to (9), inwhich a dosage form is an eye drop.

(11) The pharmaceutical preparation described in any of (1) to (10), inwhich the pharmaceutical preparation is used for a human.

(12) The pharmaceutical preparation described in any of (1) to (11), inwhich the pharmaceutical preparation is used to be instilled once ortwice a day.

(13) The pharmaceutical preparation described in any of (1) to (12), inwhich the pharmaceutical preparation is used in such a manner that adose of one or two drops is instilled.

(14) The pharmaceutical preparation described in any of (1) to (13), inwhich the pharmaceutical preparation is used to be instilled once a day.

(15) The pharmaceutical preparation described in any of (1) to (14), inwhich the pharmaceutical preparation is used in such a manner that adose of one drop is instilled.

(16) A method for treatment or prevention of glaucoma or ocularhypertension, comprising administrating the pharmaceutical preparationdescribed in any of (1) to (11) to a patient who needs the treatment orprevention of glaucoma or ocular hypertension.

(17) The method described in (16), in which the administrating isinstillation.

(18) The method for treatment or prevention of glaucoma or ocularhypertension, described in (16) or (17), in which the instillation isprovided once or twice a day.

(19) The method for treatment or prevention of glaucoma or ocularhypertension, described in (16) or (17), in which a dose of one or twodrops is instilled.

(20) The method for treatment or prevention of glaucoma or ocularhypertension, described in (16) or (17), in which a dose of one drop isinstilled once a day.

The present invention provides a pharmaceutical preparation fortreatment or prevention of glaucoma or ocular hypertension, or forlowering of intraocular pressure, in which the present compound containsthe dose described in (1) to (15) and/or is administrated according tothe usage described in (1) to (15) thereby to have an excellentintraocular pressure lowering effect for a patient, particularly ahuman.

The present invention also provides a method for treatment or preventionof glaucoma or ocular hypertension, and a method for lowering anintraocular pressure, using the pharmaceutical preparation.

The present invention further provides a method for using the presentcompound in order to prepare the pharmaceutical preparation fortreatment or prevention of glaucoma or ocular hypertension, or forlowering of intraocular pressure.

DESCRIPTION OF EMBODIMENTS

Embodiments of the present invention will be described in detail below.

Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof, contained in a therapeutic or preventive agent forglaucoma or ocular hypertension or an intraocular pressure loweringagent (hereinafter also referred to as “medicament”), according to thepresent invention, can be prepared by a method described in US PatentApplication Publication No. 2012/0190852 (Patent Literature 1), atypical method in the technical field thereof, or the like.

A salt of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatecontained in the medicament of the present invention is not particularlylimited as long as it is a pharmaceutically acceptable salt.Specifically, examples of the salt include inorganic acid salts such ashydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate;or organic acid salts such as acetate, trifluoroacetate, benzoate,oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate,methanesulfonate, ethanesulfonate, trifluoromethanesulfonate,benzenesulfonate, p-toluenesulfonate, glutamate or aspartate, preferablyhydrochloride or trifluoroacetate.

The content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof contained in the medicament of the present inventionis not particularly limited as long as it lies between 0.001 and 0.01%(w/v). Specifically, its lower limit is preferably 0.001% (w/v), morepreferably 0.0011% (w/v), still more preferably 0.0013% (w/v), orparticularly preferably 0.0015%(w/v). Its upper limit is preferably0.01% (w/v), more preferably 0.005% (w/v), still more preferably 0.003%(w/v), still much more preferably 0.0029% (w/v), more particularlypreferably 0.0027% (w/v), or most preferably 0.0025% (w/v). Moreparticularly, the content is preferably from 0.001 to 0.005% (w/v), morepreferably from 0.001 to 0.003% (w/v), still more preferably from 0.0011to 0.0030% (w/v), especially preferably from 0.0011 to 0.0029% (w/v),particularly preferably from 0.0013 to 0.0027% (w/v), or most preferablyfrom 0.0015 to 0.0025% (w/v). More specifically, the content ispreferably 0.0010% (w/v), 0.0011% (w/v), 0.0012% (w/v), 0.0013% (w/v),0.0014% (w/v), 0.0015% (w/v), 0.0016% (w/v), 0.0017% (w/v), 0.0018%(w/v), 0.0019% (w/v), 0.0020% (w/v), 0.0021% (w/v), 0.0022% (w/v),0.0023% (w/v), 0.0024% (w/v), 0.0025% (w/v), 0.0026% (w/v), 0.0027%(w/v), 0.0028% (w/v), 0.0029% (w/v), 0.0030% (w/v), 0.005% (w/v), or0.01% (w/v).

When the salt of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis contained, the content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl]pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatewith the salt released is in the above-described range.

If necessary, an additive may be used in the medicament of the presentinvention. A surfactant, a buffer, a tonicity agent, a stabilizer, apreservative, an anti-oxidant, a polymer of high-molecular weight, orthe like, for example, may be added as the additive.

A surfactant usable as an additive for medicines may be appropriatelymixed in the medicament of the present invention. Examples of thesurfactant include polyoxyethylene castor oil, polyoxyethylenehydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester,vitamin E, TPGS, polyoxyethylene fatty acid ester, polyoxyethylenepolyoxypropylene glycol, sucrose fatty acid ester, and the like.

More specifically, various polyoxyethylene castor oils having differentnumbers of polymerization of ethylene oxide may be used as thepolyoxyethylene castor oil, and the number of polymerization of ethyleneoxide is preferably from 5 to 100, more preferably from 20 to 50,particularly preferably from 30 to 40, or most preferably 35. Specificexamples of the polyoxyethylene castor oil include polyoxyl 5 castoroil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castoroil, polyoxyl 40 castor oil, and the like, and polyoxyl 35 castor oil ismost preferable.

Various polyoxyethylene hydrogenated castor oils having differentnumbers of polymerization of ethylene oxide may be used as thepolyoxyethylene hydrogenated castor oil, and the number ofpolymerization of ethylene oxide is preferably from 10 to 100, morepreferably from 20 to 80, particularly preferably from 40 to 70, or mostpreferably 60. Specific examples of the polyoxyethylene hydrogenatedcastor oil include polyoxyethylene hydrogenated castor oil 10,polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenatedcastor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like,and polyoxyethylene hydrogenated castor oil 60 is most preferable.

Examples of the polyoxyethylene sorbitan fatty acid ester includePolysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan triolate, Polysorbate 65, and thelike, and Polysorbate 80 is most preferable.

Vitamin E and TPGS are also referred to as tocopherol polyethyleneglycol 1000 succinate.

Examples of the polyoxyethylene fatty acid ester include polyoxylstearate 40, and the like.

Examples of the polyoxyethylene polyoxypropylene glycol includepolyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39)glycol, polyoxyethylene (196) polyoxypropylene (67) glycol,polyoxyethylene (20) polyoxypropylene (20) glycol, and the like.

Examples of the sucrose fatty acid ester include sucrose stearate, andthe like.

When the surfactant is mixed in the medicament of the present invention,the content of the surfactant may be appropriately adjusted according tothe type of the surfactant, or the like. Specifically, its lower limitis preferably 0.001% (w/v), more preferably 0.01% (w/v), still morepreferably 0.1% (w/v), particularly preferably 0.5% (w/v), or mostpreferably 0.8% (w/v). Its upper limit is preferably 10% (w/v), morepreferably 5% (w/v), still more preferably 4% (w/v), particularlypreferably 3% (w/v), or most preferably 2% (w/v). More specifically, thecontent is preferably from 0.001 to 10% (w/v), more preferably from 0.01to 5% (w/v), still more preferably from 0.1 to 4% (w/v), particularlypreferably from 0.5 to 3% (w/v), or most preferably from 0.8 to 2%(w/v).

A buffer usable as an additive for medicines may be appropriately mixedin the medicament of the present invention.

Examples of the buffer include phosphoric acid or a salt thereof, boricacid or a salt thereof, citric acid or a salt thereof, acetic acid or asalt thereof, carbonic acid or a salt thereof, tartaric acid or a saltthereof, ε-aminocaproic acid, trometamol, and the like. Morespecifically, examples of phosphate include sodium phosphate, sodiumdihydrogen phosphate, disodium hydrogenphosphate, potassium phosphate,potassium dihydrogenphosphate, dipotassium hydrogenphosphate, and thelike. Examples of borate include borax, sodium borate, potassium borate,and the like. Examples of citrate include sodium citrate, disodiumcitrate, trisodium citrate, and the like. Examples of acetate includesodium acetate, potassium acetate, and the like. Examples of carbonateinclude sodium carbonate, sodium hydrogencarbonate, and the like.Examples of tartrate include sodium tartrate, potassium tartrate, andthe like. Above all, the boric acid or the salt thereof or the citricacid or the salt thereof is preferable.

When the buffer is mixed in the medicament of the present invention, thecontent of the buffer may be appropriately adjusted according to thetype of the buffer, or the like. The content of the buffer is preferablyfrom 0.001 to 10% (w/v), more preferably from 0.01 to 5% (w/v), stillmore preferably from 0.1 to 3% (w/v), or most preferably from 0.2 to 2%(w/v).

A tonicity agent usable as an additive for medicines may beappropriately mixed in the medicament of the present invention.

Examples of the tonicity agent include an ionic tonicity agent, anonionic tonicity agent, and the like.

Examples of the ionic tonicity agent include sodium chloride, potassiumchloride, calcium chloride, magnesium chloride, and the like, andexamples of the nonionic tonicity agent include glycerin, propyleneglycol, sorbitol, mannitol, and the like. When the tonicity agent ismixed in the medicament of the present invention, the content of thetonicity agent may be appropriately adjusted according to the type ofthe tonicity agent, or the like. The content of the tonicity agent ispreferably from 0.01 to 10% (w/v), more preferably from 0.02 to 7%(w/v), still more preferably from 0.1 to 5% (w/v), particularlypreferably from 0.5 to 4% (w/v), or most preferably from 0.8 to 3%(w/v).

A stabilizer usable as an additive for medicines may be appropriatelymixed in the medicament of the present invention.

Examples of the stabilizer include edetic acid, monosodium edetate,disodium edetate, tetrasodium edetate, sodium citrate, and the like, anddisodium edetate is particularly preferable. Sodium edetate may be ahydrate. When the stabilizer is mixed in the medicament of the presentinvention, the content of the stabilizer may be appropriately adjustedaccording to the type of the stabilizer, or the like. The content of thestabilizer is preferably from 0.001 to 1% (w/v), more preferably from0.005 to 0.5% (w/v), or most preferably from 0.01 to 0.1% (w/v).

A preservative usable as an additive for medicines may be appropriatelymixed in the medicament of the present invention.

Examples of the preservative include benzalkonium chloride, benzalkoniumbromide, benzetonium chloride, sorbic acid, potassium sorbate, methylparaoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like.When the preservative is mixed in the medicament of the presentinvention, the content of the preservative may be appropriately adjustedaccording to the type of the preservative, or the like. The content ofthe preservative is preferably from 0.0001 to 1% (w/v), more preferablyfrom 0.0005 to 0.1% (w/v), still more preferably from 0.001 to 0.05%(w/v), or most preferably from 0.005 to 0.010% (w/v).

An anti-oxidant usable as an additive for medicines may be appropriatelymixed in the medicament of the present invention.

Examples of the anti-oxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butyl hydroxyanisole, sodium erythorbate, propylgallate, sodium sulfite, and the like. When the anti-oxidant is mixed inthe medicament of the present invention, the content of the anti-oxidantmay be appropriately adjusted according to the type of the anti-oxidant,or the like. The content of the anti-oxidant is preferably from 0.0001to 1% (w/v), more preferably from 0.0005 to 0.1% (w/v), or mostpreferably from 0.001 to 0.05% (w/v).

A polymer of high-molecular weight usable as an additive for medicinesmay be appropriately mixed in the medicament of the present invention.

Examples of the polymer of high-molecular weight include methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose,hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethylcellulose sodium, hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose,cellulose acetate phthalate, polyvinylpyrrolidone, polyvinylalcohol,carboxyvinyl polymer, polyethylene glycol, and the like.

When the polymer of high-molecular weight is mixed in the medicament ofthe present invention, the content of the polymer of high-molecularweight may be appropriately adjusted according to the type of thepolymer of high-molecular weight, or the like. The content of thepolymer of high-molecular weight is preferably from 0.001 to 5% (w/v),more preferably from 0.01 to 1% (w/v), or most preferably from 0.1 to0.5% (w/v).

The pH of the medicament of the present invention is preferably from 4.0to 8.0, more preferably from 4.5 to 7.5, particularly preferably from5.0 to 7.0, or most preferably from 5.5 to 6.5. Hydrochloric acid,phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassiumhydroxide, or the like, for example, as a pH adjusting agent foradjusting the pH, may be added to the medicament of the presentinvention.

The medicament of the present invention can be filled into and preservedin containers made of various materials. A container made ofpolyethylene, polypropylene, or the like, for example, may be used, andpreferably, the medicament of the present invention is filled into andpreserved in the container made of polyethylene from the viewpoint ofease of instillation (or hardness of the container), stability of thepresent compound, or the like.

A dosage form of the medicament of the present invention is notparticularly limited as long as it is usable for medicines.Specifically, examples of the dosage form include an eye drop, anophthalmic injection, an ophthalmic ointment, and the like, and the eyedrop is particularly preferable. These dosage forms of the medicamentcan be prepared according to ordinary methods in the art. Also, when themedicament of the present invention is a liquid medicament, it ispreferable that a solvent or a dispersion medium be water.

One aspect of the medicament of the present invention does not includeother therapeutic agents for glaucoma and is not used in combinationwith other therapeutic agents for glaucoma.

The medicament of the present invention may contain one or more,preferably one to three, or more preferably one or two other therapeuticagents for glaucoma or ocular hypertension or intraocular pressurelowering agents, and other therapeutic agents for glaucoma are notparticularly limited. Specifically, a therapeutic agent for glaucoma orthe like which is commercially available or under development ispreferable, a commercially available therapeutic agent for glaucoma orthe like is more preferable, or a commercially available therapeuticagent for glaucoma or the like which is different in function andmechanism from the present compound is particularly preferable. Morespecifically, a non-selective sympathomimetic agent, an α₂-receptoragonist, an α₁-receptor antagonist, a β-receptor antagonist, aparasympathomimetic agent, a carbonic anhydrase inhibitor, aprostaglandin, a Rho-kinase inhibitor, and the like are included.

Specific examples of the non-selective sympathomimetic agent includedipivefrin. Specific examples of the α₂-receptor agonist includebrimonidine and apraclonidine. Specific examples of the α₁-receptorantagonist include bunazosin. Specific examples of the β-receptorantagonist include timolol, befunolol, carteolol, nipradilol, betaxolol,levobunolol and metipranolol. Specific examples of theparasympathomimetic agent include pilocarpine. Specific examples of thecarbonic anhydrase inhibitor include dorzolamide, brinzolamide andacetazolamide. Specific examples of the prostaglandin includelatanoprost, isopropyl unoprostone, bimatoprost and travoprost. Specificexamples of the Rho-kinase inhibitor include ripasudil.

The usage of the medicament of the present invention is not particularlylimited as long as it is sufficient to achieve a desired pharmacologicaleffect, and the usage of the medicament may be appropriately selectedaccording to symptoms of a disease, the age or body weight of a patient,the dosage form of the medicament, or the like.

Specifically, a dose of one to five drops, preferably one to threedrops, more preferably one or two drops, or particularly preferably onedrop may be instilled every day through every week one to four times aday, preferably one to three times a day, more preferably once or twicea day, or particularly preferably once a day. Preferably, a dose of onedrop is instilled every day once a day. Here, one drop is typically fromabout 0.01 to about 0.1 mL, preferably from about 0.015 to about 0.07mL, more preferably from about 0.02 to about 0.05 mL, or particularlypreferably from about 0.03 mL.

The medicament of the present invention refers to a therapeutic orpreventive agent, and more specifically to a therapeutic or preventiveagent for glaucoma, a therapeutic or preventive agent for ocularhypertension, or an intraocular pressure lowering agent.

Glaucoma in the present invention includes primary open angle glaucoma,secondary open angle glaucoma, normal tension glaucoma, hypersecretionglaucoma, primary angle-closure glaucoma, secondary angle-closureglaucoma, plateau iris glaucoma, combined-mechanism glaucoma,developmental glaucoma, steroid-induced glaucoma, exfoliation glaucoma,amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsularglaucoma, plateau iris syndrome, and the like, or preferably primaryopen angle glaucoma, normal tension glaucoma, and primary angle-closureglaucoma, and the pharmaceutical preparation of the present invention isparticularly effective for primary open angle glaucoma.

EXAMPLES

Although preparation examples and clinical test results will be givenbelow, they are for purposes of a better understanding of the presentinvention and are not intended to limit the scope of the presentinvention.

PREPARATION EXAMPLES

Representative preparation examples of the medicament of the presentinvention will be given below. In the following preparation examples,the amounts of ingredients mixed are the contents thereof in 100 mL of apreparation. The present compound A refers to isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate.

Preparation Example 1

Eye Drop (in 100 mL) Present compound A 0.002 g Boric acid  0.2 gGlycerin  2.0 g Polysorbate 80  0.5 g Disodium edetate  0.05 gBenzalkonium chloride 0.005 g Diluted hydrochloric acid q.s. Sodiumhydroxide q.s. Purified water q.s.

Preparation Example 2

Eye Drop (in 100 mL) Present compound A 0.002 g Sodium dihydrogenphosphate  0.2 g Glycerin  2.0 g Vitamin E, TPGS  0.8 g Disodium edetate 0.05 g Benzalkonium chloride 0.005 g Diluted hydrochloric acid q.s.Sodium hydroxide q.s. Purified water q.s.

Preparation Example 3

Eye Drop (in 100 mL) Present compound A 0.002 g Trisodium citrate  0.2 gGlycerin  2.0 g Polyoxyethylene hydrogenated castor oil 60  0.3 gDisodium edetate  0.05 g Benzalkonium chloride 0.005 g Dilutedhydrochloric acid q.s. Sodium hydroxide q.s. Purified water q.s.

In Preparation Examples 1 to 3, a medicament can be obtained byappropriately adjusting the type and/or mixed amount of the presentcompound A and/or the additive.

1. Clinical Test (1)

1-1. Preparation of Eye Drop

Eye drops 1 and 2 and a placebo eye drop given in Table 1 were prepared.

TABLE 1 Placebo eye % (w/v) Eye drop 1 Eye drop 2 drop Present 0.0030.01 — compound A Disodium 0.05 0.05 0.05 edetate dihydrate Sorbic acid0.1 0.1 0.1 Polyoxyl 35 0.8 1.7 5 castor oil Boric acid 1 1 1 Glycerin 11 1 Benzalkonium 0.01 0.01 0.01 chloride HCl/NaOH q.s. q.s. q.s.Purified q.s. q.s. q.s. water pH About 6.5 About 6.5 About 6.5

1-2. Test Method

For primary open angle glaucoma patients (26 persons) or ocularhypertension patients (18 persons), one drop (about 0.03 ml) of the eyedrops 1 and 2 or the placebo eye drop was instilled once a day for fourweeks.

1-3. Test Results and Discussion

An average intraocular pressure change (mmHg) from before the start ofinstillation of the eye drops 1 and 2 (or a base line), after a lapse of16 hours after the last instillation, was calculated as a differencefrom an average intraocular pressure change of the placebo eye drop.Results are shown in Table 2.

TABLE 2 Average intraocular pressure change (mmHg) after a lapse of 16hours after the last instillation (relative to placebo eye drop) Eyedrop 1 −4.6 Eye drop 2 −2.5

As is apparent from Table 2, the eye drop 1 (0.003%) and the eye drop 2(0.01%) both exhibit an intraocular pressure lowering effect, andexhibited a more excellent intraocular pressure lowering effect when thecontent of the present compound A is 0.003% (w/v). On the contrary toexpectation of those skilled in the art, a significantly low content ofthe present compound A exhibited a higher intraocular pressure loweringeffect.

2. Clinical Test (2)

2-1. Preparation of Eye Drop

Eye drops 3 to 6 and a placebo eye drop given in Table 3 were prepared.The eye drop 3 contains 0.0003% (w/v) of the present compound A and thusis Reference Example of the present invention.

TABLE 3 Eye drop Eye Eye Eye Placebo % (w/v) 3 drop 4 drop 5 drop 6 eyedrop Present 0.0003 0.001 0.002 0.003 — compound A Disodium 0.02 0.020.02 0.02 0.02 edetate dehydrate Polyoxyl 35 0.8 0.8 0.8 0.8 0.8 castoroil Boric acid 1 1 1 1 1 Glycerin 1 1 1 1 1 Benzalkonium 0.01 0.01 0.010.01 0.01 chloride HCl/NaOH q.s. q.s. q.s. q.s. q.s. Purified q.s. q.s.q.s. q.s. q.s. water pH About 6 About 6 About 6 About 6 About 6

2-2. Test Method

For primary open angle glaucoma patients (37 persons) or ocularhypertension patients (39 persons), one drop (about 0.03 ml) of the eyedrops 3 to 6 or the placebo eye drop was instilled once a day for fourweeks.

2-3. Test Results and Discussion

An average intraocular pressure change (mmHg) from before the start ofinstillation of the eye drops 3 to 6 (or a base line), after a lapse of16 hours after the last instillation, was calculated as a differencefrom an average intraocular pressure change of the placebo eye drop.Results are shown in Table 4.

TABLE 4 Average intraocular pressure change (mmHg) after a lapse of 16hours after the last instillation (relative to placebo eye drop) Eyedrop 3 −1.9 Eye drop 4 −3.1 Eye drop 5 −5.2 Eye drop 6 −4.0

As is apparent from Table 4, the eye drops 4 to 6 all exhibited a higherintraocular pressure lowering effect than the eye drop 3. Therefore,when the content of the present compound A is from 0.001 to 0.003% (w/v)like the eye drops 4 to 6, a particularly excellent intraocular pressurelowering effect was exhibited. Moreover, the eye drops 4 to 6 weresufficiently permissible as medicines also in terms of side effects.

The invention claimed is:
 1. A liquid pharmaceutical preparation fortreatment or prevention of glaucoma or ocular hypertension, comprising0.001 to 0.003% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, or a salt thereof; and water. 2.A liquid pharmaceutical preparation for treatment or prevention ofglaucoma or ocular hypertension, comprising 0.002% (w/v) of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, or a salt thereof; and water. 3.The liquid pharmaceutical preparation according to claim 1, in which thepreparation is for treatment of glaucoma.
 4. The liquid pharmaceuticalpreparation according to claim 1, in which the preparation is fortreatment of ocular hypertension.
 5. The liquid pharmaceuticalpreparation according to claim 1, in which the preparation does notinclude other therapeutic agents for glaucoma.
 6. The liquidpharmaceutical preparation according to claim 1, in which thepreparation is not used in combination with other therapeutic agents forglaucoma.
 7. An eye drop comprising the liquid pharmaceuticalpreparation of claim
 1. 8. A method for treatment or prevention ofglaucoma or ocular hypertension, comprising administrating the liquidpharmaceutical preparation of claim 1 to a patient who needs thetreatment or prevention of glaucoma or ocular hypertension.
 9. A methodfor treatment of glaucoma, comprising administrating the liquidpharmaceutical preparation of claim 3 to a patient who needs thetreatment of glaucoma.
 10. A method for treatment of ocularhypertension, comprising administrating the liquid pharmaceuticalpreparation of claim 4 to a patient who needs the treatment of ocularhypertension.
 11. The method of claim 8, in which the liquid preparationdoes not include other therapeutic agents for glaucoma.
 12. The methodof claim 8, the liquid preparation is not used in combination with othertherapeutic agents for glaucoma.
 13. The method of claim 8, in which theadministrating is instillation.
 14. The method of claim 13, in which theinstillation is provided once or twice a day.
 15. The method of claim 8,in which a dose of one or two drops is instilled.
 16. The method ofclaim 8, in which a dose of one drop is instilled once a day.
 17. Themethod of claim 8, wherein the patient is a human.